HRP20160136T1 - Peptide-mediated non-covalent delivery of active agents across the blood brain barrier - Google Patents

Peptide-mediated non-covalent delivery of active agents across the blood brain barrier Download PDF

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HRP20160136T1
HRP20160136T1 HRP20160136TT HRP20160136T HRP20160136T1 HR P20160136 T1 HRP20160136 T1 HR P20160136T1 HR P20160136T T HRP20160136T T HR P20160136TT HR P20160136 T HRP20160136 T HR P20160136T HR P20160136 T1 HRP20160136 T1 HR P20160136T1
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peptide
agent
carrier
brain barrier
blood
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HRP20160136TT
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Geoffry L. Curran
Gobinda Sarkar
Joseph F. Poduslo
Robert B. Jenkins
Val J. Lowe
Eric W. Mahlum
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Mayo Foundation For Medical Education And Research
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/775—Apolipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
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    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0058—Antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1018—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01023—Beta-galactosidase (3.2.1.23), i.e. exo-(1-->4)-beta-D-galactanase
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Claims (11)

1. Peptid nosač koji sadrži sekvencu:Xn-[B]mili njegova farmaceutski prihvatljiva sol, naznačen time da: X je hidrofilna amino kiselina;B je sredstvo za krvno-moždanu barijeru;n je cijeli broj od 4 do 50; i m je cijeli broj od 1 do 3;pri čemu sredstvo za krvno-moždanu barijeru sadrži polipeptidnu sekvencu koja ima barem 80% identičnosti sekvence sa: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13).1. Peptide carrier containing the sequence: Xn-[B]mili its pharmaceutically acceptable salt, indicated that: X is a hydrophilic amino acid; B is an agent for the blood-brain barrier; n is an integer from 4 to 50; and m is an integer from 1 to 3; wherein the blood-brain barrier agent comprises a polypeptide sequence having at least 80% sequence identity to: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13). 2. Peptid nosač prema zahtjevu 1, naznačen time da svaki X je neovisno odabran od arginina, asparagina, asparaginske kiseline, glutaminske kiseline, glutamina, histidina, lizina, serina, treonina, i tirozina, ili pri čemu n je odabran od 4, 8, 12, 16, i 20, ili pri čemu m je 1.2. Peptide carrier according to claim 1, characterized in that each X is independently selected from arginine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, lysine, serine, threonine, and tyrosine, or wherein n is selected from 4, 8 , 12, 16, and 20, or where m is 1. 3. Peptid nosač prema zahtjevu 1, naznačen time da polipeptid ima duljinu od manje od 100 amino kiselina.3. Peptide carrier according to claim 1, characterized in that the polypeptide has a length of less than 100 amino acids. 4. Peptid nosač prema zahtjevu 1, naznačen time da je peptid nosač odabran od: K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:19); K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:20);K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:21);K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:22);K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:23).4. Peptide carrier according to claim 1, characterized in that the peptide carrier is selected from: K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:19); K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:20);K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:21);K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:22);K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:23). 5. Kompleks, ili njegova farmaceutski prihvatljiva sol, naznačen time da sadrži biološki aktivnu molekulu ili kontrastno sredstvo povezano s peptidom nosačem prema jednom od prethodnih zahtjeva.5. The complex, or its pharmaceutically acceptable salt, characterized in that it contains a biologically active molecule or a contrast agent associated with a carrier peptide according to one of the preceding claims. 6. Kompleks prema zahtjevu 5, naznačen time da je kontrastno sredstvo odabrano od: 125I-IgG i magnevista.6. Complex according to claim 5, characterized in that the contrast agent is selected from: 125I-IgG and magnevist. 7. Kompleks prema zahtjevu 5, naznačen time da biološki aktivna molekula je odabrana od: polipeptida; oligonukleotida; plazmida; male molekule; antitijela; fragmenta antitijela; ugljikohidrata; polisaharida; lipida; glikolipida; antigena; te antigenog peptida, naročito pri čemu je oligonukleotid odabran od: kodirajuće DNA sekvence; anti-sensne DNA sekvence; mRNA, antisense RNA sekvence; RNAi; te siRNA, ili pri čemu mala molekula je terapeutsko sredstvo.7. Complex according to claim 5, characterized in that the biologically active molecule is selected from: polypeptide; oligonucleotides; plasmid; small molecules; antibodies; antibody fragments; carbohydrates; polysaccharide; lipids; glycolipids; antigens; and an antigenic peptide, especially where the oligonucleotide is selected from: a coding DNA sequence; anti-sense DNA sequences; mRNA, antisense RNA sequences; RNAi; and siRNA, or where a small molecule is a therapeutic agent. 8. Kompleks prema zahtjevu 5, naznačen time da je biološki aktivna molekula ili kontrastno sredstvo ne-kovalentno vezano na peptid nosač.8. Complex according to claim 5, characterized in that the biologically active molecule or contrast agent is non-covalently bound to the peptide carrier. 9. Kompleks, ili njegova farmaceutski prihvatljiva sol, koji sadrži biološki aktivno sredstvo povezano s peptidom nosačem, pri čemu peptid nosač sadrži sekvencu: Xn - [B]mpri čemu:X je hidrofilna amino kiselina;B je sredstvo za krvno-moždanu barijeru;n je cijeli broj od 4 do 50; i m je cijeli broj od 1 do 3,pri čemu sredstvo za krvno-moždanu barijeru sadrži polipeptidnu sekvencu koja ima barem 80% identičnosti sekvence sa: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13), naznačen time da je za liječenje poremećaja mozga, naročito pri čemu je poremećaj mozga odabran od: meningitisa, epilepsije, multiple skleroze, optičkog neuromijelitisa, kasnog stupnja neurološke tripanosomijaze, Parkinsonove, progresivne multifokalne leukoencefalopatije, De Vivo bolesti, Alzheimerove bolesti, HIV encefalitisa, i raka. Postupak za prikazivanje središnjeg živčanog sustava kod subjekta, te postupak obuhvaća davanje subjektu kompleksa, ili njegove farmaceutski prihvatljive soli, koji sadrži kontrastno sredstvo povezano s peptidom nosačem, pri čemu peptid nosač sadrži sekvencu:Xn - [B]mpri čemu: X je hidrofilna amino kiselina; B je sredstvo za krvno-moždanu barijeru; n je cijeli broj od 4 do 50; i m je cijeli broj od 1 do 3; i prikazivanje središnjeg živčanog sustava subjekta, pri čemu sredstvo za krvno-moždanu barijeru sadrži polipeptidnu sekvencu koja ima barem 80% identičnosti sekvence sa: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13).9. A complex, or a pharmaceutically acceptable salt thereof, containing a biologically active agent associated with a carrier peptide, wherein the carrier peptide contains the sequence: Xn - [B]mwherein: X is a hydrophilic amino acid; B is an agent for the blood-brain barrier; n is an integer from 4 to 50; and m is an integer from 1 to 3, wherein the agent for the blood-brain barrier contains a polypeptide sequence that has at least 80% sequence identity with: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13), indicated that it is for the treatment of brain disorders, in particular where is a brain disorder selected from: meningitis, epilepsy, multiple sclerosis, neuromyelitis optica, late stage neurological trypanosomiasis, Parkinson's, progressive multifocal leukoencephalopathy, De Vivo disease, Alzheimer's disease, HIV encephalitis, and cancer. A method for imaging the central nervous system in a subject, and the method comprises administering to the subject a complex, or a pharmaceutically acceptable salt thereof, containing a contrast agent associated with a carrier peptide, wherein the carrier peptide contains the sequence: Xn - [B]mwherein: X is a hydrophilic amino acid; B is an agent for the blood-brain barrier; n is an integer from 4 to 50; and m is an integer from 1 to 3; and showing the subject's central nervous system, wherein the blood-brain barrier agent comprises a polypeptide sequence having at least 80% sequence identity to: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13). 10. Farmaceutski pripravak naznačen time da sadrži kompleks, ili njegovu farmaceutski prihvatljivu sol, koji sadrži biološki aktivnu molekulu ili kontrastno sredstvo, peptid nosač, i farmaceutski prihvatljiv nosač; pri čemu peptid nosač sadrži sekvencu: Xn - [B]mpri čemu: X je hidrofilna amino kiselina; B je sredstvo za krvno-moždanu barijeru; n je cijeli broj od 4 do 50; i m je cijeli broj od 1 do 3, pri čemu sredstvo za krvno-moždanu barijeru sadrži polipeptidnu sekvencu koja ima barem 80% identičnosti sekvence sa: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13).10. A pharmaceutical preparation characterized by the fact that it contains a complex, or its pharmaceutically acceptable salt, which contains a biologically active molecule or a contrast agent, a peptide carrier, and a pharmaceutically acceptable carrier; wherein the carrier peptide contains the sequence: Xn - [B]mwhere: X is a hydrophilic amino acid; B is an agent for the blood-brain barrier; n is an integer from 4 to 50; and m is an integer from 1 to 3, wherein the blood-brain barrier agent comprises a polypeptide sequence having at least 80% sequence identity to: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13). 11. Komplet (kit) koji sadrži peptid nosač, naznačen time da peptid nosač sadrži sekvencu: Xn - [B]mili njegovu farmaceutski prihvatljivu sol, pri čemu: X je hidrofilna amino kiselina; B je sredstvo za krvno-moždanu barijeru; n je cijeli broj od 4 do 50; i m je cijeli broj od 1 do 3, pri čemu sredstvo za krvno-moždanu barijeru sadrži polipeptidnu sekvencu koja ima barem 80% identičnosti sekvence sa: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13)., pri čemu komplet dodatno sadrži biološki aktivnu molekulu ili kontrastno sredstvo.11. A kit containing a peptide carrier, characterized in that the peptide carrier contains the sequence: Xn - [B] or its pharmaceutically acceptable salt, wherein: X is a hydrophilic amino acid; B is an agent for the blood-brain barrier; n is an integer from 4 to 50; and m is an integer from 1 to 3, wherein the agent for the blood-brain barrier contains a polypeptide sequence having at least 80% sequence identity with: L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:13), wherein the kit additionally contains a biologically active molecule or a contrast agent .
HRP20160136TT 2009-07-14 2016-02-05 Peptide-mediated non-covalent delivery of active agents across the blood brain barrier HRP20160136T1 (en)

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US22541209P 2009-07-14 2009-07-14
PCT/US2010/041924 WO2011008823A2 (en) 2009-07-14 2010-07-14 Peptide-mediated non-covalent delivery of active agents across the blood brain barrier
EP10800456.5A EP2453923B1 (en) 2009-07-14 2010-07-14 Peptide-mediated non-covalent delivery of active agents across the blood brain barrier

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